Preclinical studies involving immunotherapeutic strategies for central nervous system (CNS) tumors, such as glioblastoma multiforme (GBM), have demonstrated that tumor-specific T helper type-1 (Th1) and T cytotoxic type-1 (Tc1) cells, but not type-2 counterparts, can efficiently traffic into CNS tumor sites and mediate effective therapeutic efficacy, recruited via the type-1 chemokine CXCL10 (Nishimura et al., Cancer Res 2006, 66:4478-4487; Fujita et al., J Immunol 2008, 180:2089-2098; Fujita et al., Cancer Res 2009, 69:1587-1595) and the integrin receptor, very late antigen (VLA)-4 (Sasaki et al., The Journal of Immunology 2008, 181:104-108; Sasaki et al., Eur J Immunol 2008, 38:2865-2873; Zhu et al., J Transl Med 2007, 5:10; Sasaki et al., Cancer Res 2007, 67:6451-6458). Despite the importance of the type-1 T cell response, cancers, including GBMs, secrete numerous type-2 cytokines (Roussel et al., Clin Exp Immunol 1996, 105:344-352; Weller and Fontana, Brain Res 1995, 21:128-151; Nitta et al., Brain Res 1994, 649:122-128) that promote tumor proliferation (Jarnicki et al., J Immunol 2006, 177:896-904; Prokopchuk et al., Br J Cancer 2005, 92:921-928) and immune escape (Seo et al., Immunology 2001, 103:449-457). Hence, the strategic skewing of existing type-2 to type-1 immunity in glioma patients may be critical for the development of more effective immunotherapy.
MicroRNAs (miRs) are a novel class of endogenous small single-stranded RNA molecules which are 18-24 nucleotides in length (Hammond, Cancer Chemother Pharmacol 2006, 58 Suppl 1:s63-68). Mature miRs repress mRNA encoded protein translation and are highly conserved between species, including viruses, plants and animals (Elmen Nature 2008, 452:896-899). There are over 700 miRs identified in the human genome that collectively are predicted to regulate two-thirds of all mRNA transcripts (Hammond, Cancer Chemother Pharmacol 2006, 58 Suppl 1:s63-68). Findings over the past several years strongly support a role for miRs in the regulation of crucial biological processes, such as cellular proliferation (Cheng et al., Nucleic Acids Res 2005, 33:1290-1297), apoptosis (Xu et al., Trends Genet. 2004, 20:617-624), development (Karp and Ambros, Science 2005, 310:1288-1289), differentiation (Chen et al., Science 2004, 303:83-86), metabolism (Poy et al., Nature 2004, 432:226-230), and immune regulation (That et al., Science 2007, 316:604-608; O'Connell et al., Proc Natl Acad Sci USA 2007, 104:1604-1609). A recent study demonstrated that miR-222 and miR-339 in cancer cells down-regulate the expression of an intercellular cell adhesion molecule (ICAM)-1, thereby regulating the susceptibility of cancer cells to cytotoxic T lymphocytes (CTLs) (Ueda et al., Proc Natl Acad Sci USA 2009, 106:10746-10751). This is among the first reports to demonstrate the role of miR in cancer immunosurveillance.